Francesca P. A. Fabbiani

An exploration of the polymorphism of piracetam using high pressure

High-pressure recrystallisation of aqueous and methanolic solutions of piracetam (2-oxo-pyrrolidineacetamide) contained in a diamond-anvil cell at pressures of 0.07–0.4 GPa resulted in the formation of a new high-pressure polymorph of piracetam that has been characterised by in situ X-ray diffraction. The molecular packing arrangement of the new form is very different from those of forms I, II, and III, and the piracetam molecules also adopt a very different conformation in this new phase. Depressurisation to ambient pressure resulted in the formation of form II via a single-crystal to single-crystal transition. By contrast, crystallisation of piracetam from water at ambient pressure resulted in the formation of a new monohydrate of piracetam, which has been characterised by single crystal X-ray diffraction.

High-pressure recrystallisation—a route to new polymorphs and solvates

The recrystallisation of organic compounds from solution under high-pressure conditions is shown to be a versatile method for the formation of new polymorphs and solvates. The technique is illustrated by the crystallisation of a new polymorph of phenanthrene from dichloromethane at a pressure of 0.7 GPa, and the crystallisation of a novel dihydrate of paracetamol from water at a pressure of 1.1 GPa. These phases have been characterised by single crystal X-ray diffraction. We also demonstrate that the technique can be used to prepare a polymorph that is metastable under ambient conditions. Thus the orthorhombic form of paracetamol was crystallised from ethanol at a pressure of 1.1 GPa.

Combined crystal structure prediction and high-pressure crystallization in rational pharmaceutical polymorph screening

Organic molecules, such as pharmaceuticals, agro-chemicals and pigments, frequently form several crystal polymorphs with different physicochemical properties. Finding polymorphs has long been a purely experimental game of trial-and-error. Here we utilize in silico polymorph screening in combination with rationally planned crystallization experiments to study the polymorphism of the pharmaceutical compound Dalcetrapib, with 10 torsional degrees of freedom one of the most flexible molecules ever studied computationally. The experimental crystal polymorphs are found at the bottom of the calculated lattice energy landscape, and two predicted structures are identified as candidates for a missing, thermodynamically more stable polymorph. Pressure-dependent stability calculations suggested high pressure as a means to bring these polymorphs into existence. Subsequently, one of them could indeed be crystallized in the 0.02 to 0.50 GPa pressure range and was found to be metastable at ambient pressure, effectively derisking the appearance of a more stable polymorph during late-stage development of Dalcetrapib.

Solvent inclusion in the structural voids of form II carbamazepine: single-crystal X-ray diffraction, NMR spectroscopy and Hirshfeld surface analysis

Single-crystal X-ray diffraction and solution 1H NMR spectroscopy, in conjunction with Hirshfeld surface analysis, give evidence of solvent inclusion in the trigonal polymorph of carbamazepine, which in the unsolvated form is characterised by the presence of large structural voids.

Ruthenium(II) arene anticancer complexes with redox-active diamine ligands

The synthesis and characterization of ruthenium(II) arene complexes of the general formula [(eta(6)-arene)Ru(XY)Z](+), where arene = p-cymene (p-cym), hexamethylbenzene (hmb), or biphenyl (bip), XY = o-phenylenediamine (o-pda), o-benzoquinonediimine (o-bqdi), or 4,5-dimethyl-o-phenylenediamine (dmpda), and Z = Cl, Br, or I, are reported (complexes 1-6). In addition, the X-ray crystal structures of [(eta(6)-p-cym)Ru(o-pda)Cl]PF(6) (1) and [(eta(6)-hmb)Ru(o-bqdi)Cl]PF(6) (3PF(6)) are described. The Ru-N distances in 3PF(6) are significantly shorter [2.033(4) and 2.025(4) A] compared to those in 1 [2.141(2) and 2.156(2) A]. All of the imine complexes (3-5) exhibit a characteristic broad (1)H NMR NH resonance at ca. delta 14-15. Complex 1 undergoes concomitant ligand-based oxidation and hydrolysis (38% after 24 h) in water. The oxidation also occurs in methanol. The iodido complex [(eta(6)-p-cym)Ru(o-bqdi)I]I (4) did not undergo hydrolysis, whereas the chlorido complex 3 showed relatively fast hydrolysis (t(1/2) = 7.5 min). Density functional theory calculations showed that the total bonding energy of 9-EtG in [(eta(6)-p-cym)Ru(o-pda)(9-EtG-N7)](2+) (1EtG) is 23.8 kJ/mol lower than that in [(eta(6)-p-cym)Ru(o-bqdi)(9-EtG-N7)](2+) (3EtG). The greater bonding energy is related to the contribution from strong hydrogen bonding between the NH proton of the chelating ligand and O6 of 9-EtG (1.69 A). A loss of cytotoxic activity was observed upon oxidation of the amine ligand to an imine (e.g., IC(50) = 11 microM for 1 and IC(50) > 100 microM for 3, against A2780 ovarian cancer cells). The relationship between the cytotoxic activity and the solution and solid state structures of the imine and amine complexes is discussed.

The Monoammoniate of Lithium Borohydride, Li(NH3)BH4: An Effective Ammonia Storage Compound

Lithium borohydride absorbs anhydrous ammonia to form four stable ammoniates; Li(NH(3))(n)BH(4), mono-, di-, tri-, and tertraammoniate. This paper focuses on the monoammoniate, Li(NH(3))BH(4), which is readily formed on exposure of LiBH(4) to ammonia at room temperature and pressure. Ammonia loss from Li(NH(3))BH(4) commences around 40 degrees C and the compound transforms directly to LiBH(4). The crystal structure of Li(NH(3))BH(4) is reported here for the first time. Its close structural relationship with LiBH(4) provides a clear insight into the facile nature and mechanism of ammonia uptake and loss. These materials not only represent an excellent high weight-percent ammonia system but are also potentially important hydrogen stores.

Crystal structures with a challenge: high-pressure crystallisation of ciprofloxacin sodium salts and their recovery to ambient pressure

Two novel sodium salts of the antibiotic ciprofloxacin were crystallised at pressures of 0.25 and 0.6 GPa and subsequently recovered to ambient pressure. The structures are the first reported examples of ciprofloxacin chelating a Group IA monovalent cation. Ambient-pressure crystallisation of the same solution used for high-pressure experiments, yielded crystals of the known hexahydrate. In a parallel study, the previously unknown structure of anhydrous ciprofloxacin was determined from powder diffraction data. The structures are described and compared using the XPac method.

Putting pressure on elusive polymorphs and solvates

The reproducible crystallisation of elusive polymorphs and solvates of molecular compounds at high pressure has been demonstrated through studies on maleic acid, malonamide, and paracetamol. These high-pressure methods can be scaled-up to produce ‘bulk’ quantities of metastable forms that can be recovered to ambient pressure for subsequent seeding experiments. This has been demonstrated for paracetamol form II and paracetamol monohydrate. The studies also show that the particular solid form can be tuned by both pressure and concentration.

Searching for novel crystal forms by in situ high-pressure crystallisation: the example of gabapentin heptahydrate

High-pressure crystallisation of an aqueous solution of the GABA analogue gabapentin at 0.8 GPa resulted in the formation of a previously unknown heptahydrate form, whose structure has been determined by in situ single-crystal X-ray diffraction. The structure and water framework of this unusually highly hydrated small molecule are described in detail.

Controlling the reactivity of ruthenium(II) arene complexes by tether ring-opening

The closed- and open-tethered Ru(II) eta(6)-arene complexes [Ru(II)(eta(6):eta(1)-C(6)H(5)(C(6)H(4))NH(2))(en)]Cl(2) (2) and [Ru(II)(eta(6)-C(6)H(5)(C(6)H(4))NH(2))Cl(en)]Cl (3), where en is ethylenediamine, have been synthesized and their X-ray structures determined. Interconversion between 2 and 3, that is, tethered-arene ring-closure and ring-opening, in different solvents has been investigated. Complex 2 opens in dimethylsulfoxide (DMSO) by solvent-induced dissociation of the NH(2) group of the pendant arm. In methanol, however, equilibrium between 2 and 3 is reached after 12 h when both species coexist in solution in a ratio of 2:1 (open/closed). In water (pH 7), complete ring closure of 3 to 2 at 298 K occurs in less than 2 h. The tether ring of complex 2 opens at basic pH and closes at neutral pH. Complex 2 opens over time (18 h) in concentrated HCl. The opening-closing process is fully reversible in the pH range 2-12. Density Functional Theory calculations have been used to obtain insights into the electronic structure of complexes 2 and 3, their UV-vis properties, and their stability compared to their aqua derivatives. Control of tether-ring-opening can contribute toward a strategy for activation and for achieving cytotoxic selectivity of ruthenium arene anticancer drugs.